CA1252470A - Tetrahydropyridines, process for their preparation and their use in medicaments - Google Patents
Tetrahydropyridines, process for their preparation and their use in medicamentsInfo
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- CA1252470A CA1252470A CA000439471A CA439471A CA1252470A CA 1252470 A CA1252470 A CA 1252470A CA 000439471 A CA000439471 A CA 000439471A CA 439471 A CA439471 A CA 439471A CA 1252470 A CA1252470 A CA 1252470A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
- C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D211/78—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/12—Antihypertensives
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Abstract
ABSTRACT
1,2,3,4-Tetrahydropyridines of the formula
1,2,3,4-Tetrahydropyridines of the formula
Description
12~4~7(1 23l~9-56l0 The present invention relates to new tetrahydropyridines, to a process for their preparation and to their use in medicaments, especially in agents affecting the circulationO
The new 1,2,3,4-tetrahydropyridines are characterized by the general formula I
R O2C ~ ~I) in which X represents the nitrile group or the radical -COOR6, R being defined below, R represents phenyl, naphthyl or pyridyl, the phenyl or naphthyl ring being optionally substituted by 1 or 2 identical or different substituents from the group consisting of phenyl, straight-chain or branched alkyl having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, tri-tetra-and pentamethylene, dioxamethylene, halogen, -trifluoromethyl, trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy and cyano, R2 represents a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 20 carbon atoms, which is optionally interrupted by one oxygen or sulphur atom in the chain and/or which is optionally substituted by halogen, cyano, hydroxyl, ~,-,~- or ~-pyridyl, phenyl, phenoxy or phenylthio, it being possible for the phenyl groups to be substituted by halogen, cyano, dialkylamino having 1 to 4 carbon atoms in each alkyl radical, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, trifluoromethyl l~S~O
or trifluoromethoxy, or by an amino group which in turn is sub-stituted by two identical or different substituents from the group consisting of alkyl having 1 to 4 carbon atoms, phenyl or benzyl, R3 and R5, which are identical or different, each repre-sent hydrogen, a straight-chain or branched alkyl radical having up to 4 carbon atoms, a phenyl radical or a benzyl radical, and R4 represents hydrogen, a straight-chain or branched alkyl radical having up to 4 carbon atoms which is optionally interrupted by an oxygen atom, a phenyl radical or a benzyl radical, Rb, when present, is as defined for R~andmaybe the same as or different from R , or a salt thereof with a physiologically tolerated acid, and their salts with physiologically tolerated acids.
Furthermore, it has been found that the compounds of the formula (I) according to the invention are obtained when dihydropyridine compounds of the formula (II) I R
R O2C ~ ~ X
~ [) R Y \ N~ R5 in which R , R2, R3, R , R5 and X have the abovementioned meaning, are electrochemically reduced at a cathode in the presence of a suitable electrolyte system.
In the case where R4 in formula (I) denotes hydrogen, it is also possible to use, as the starting material for the electrochemical reduction, the pyrdine derivatives of the '7(;~
- 2a - 23189-5610 formula ( III ), Rl R O2C ~ X
l ~ I I I ) R3~ ~ N~ ~ R5 -` lZS;~'7~3 ;n which the substituents R1, R2, R3, R5 and X have the abovementioned mean;ng.
The 1,2,3,4-tetrahydropyridine derivat;ves accord-ing to the invention have valuable pharmacological pro-perties. Because of their effect on the circulation, they can be used as antihypertensive agents, as peri-pheral and cerebral vasodilators and as coronary thera-peutic agents and thus are to be regarded as an enrich-ment of pharmacy.
Depending on the nature of the starting materialsused, the preparation of the compounds according to the invention can be represented by the following react;on schemes in which dimethyl 2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate may be chosen as an example:
H ~ CO ~ C ~ CO~ CH~ 2el3~ 2H~H ~ CO~ C ~ CO ~ CH
Hg- cathode H3 C N CH, El, C H C~I, B) H3CO2C~ ¢ ~ CO2CH3 4e~,4H~H,CO2C ~ CO2CH3 N Hg-cathode N ~
H3C CH, H3C H CH3 According to process A, a 1,4-dihydropyridine derivative of the general formula (II) Le_A 21 974 4 l~s~'~L7~3 23l8g-56l0 3 J`~ S R3 X` II~RS
(II) (I~
is converted on a mercury cathode in a suitable electrolyte system into a 1,2,3,4-tetrahydropyridine derivative of the formula (I) according to the invention.
Compounds of the general formula (I) are of particular interest in which R1 represents phenyl or pyridyl, the phenyl ring optionally being substituted by one or two identical or different substituents from the group comprising fluorine, chlorine, cyano, trifluoro-methyl, trifluoromethoxy, alkyl having 1 to 4 C atoms, alkoxy having 1 to 2 C atoms t tetramethylene or phenyl, R2 represents a straiyht-chain or branched cyclic alkyl or alkenyl radical having up to 12 carbon atoms which is optionally interrupted by an oxy-1~5~
gen atom ;n the cha;n and/or wh;ch ;s opt;onally subst;tuted by ~luorine, chlorine, cyano, hydroxyl, phenyl, phenoxy or an am;no group which in turn ;s subst;tuted by two ;dentical or different sub-stituents from the group comprising alkyl hav;ng 1 to 4 C atoms or benzyl, R3 and R5 are ident;cal or d;fferent and each re-present alkyl hav;ng 1 to 2 C atoms, R4 represents hydrogen, alkyl having 1 to 4 C
atoms or benzyl and X represents the nitrile group or represents the radical -C02R6, R6 having the mean;ng of R2 and be;n~ identical to or different from R2.
The derivatives of the general formulae (II) and (III~ used as start;ng materials are known from the lit-erature or can be prepared by methods known from the literature tcompare, for example, U. Eisner and J. Kuthan, Chem. Rev. 72, 1 (1972); E. Wehinger, F. Bossert, G.
Franckowiak and H. Meyer, German Offenlegungsschr;ft (6erman Publ;shed Specification) 2,658,804, publication date: 6.7.1978).
The following may be mentioned as examples:
diethyl 1,4-dihydro-2,6-dimethyl-4-(3-chlorophenyl)-pyri-dine-3,5-dicarboxylate, d;-(n~-butyl 1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine 3,5-dicarboxylate, dihexyl 1,4-d;hydro-2,6-dimethyl-4-(2-chlorophenyl)-pyr;
dine-3,5-dicarboxylate, didecyl 1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)~pyri-dine-3,5-dicarboxylate, diisopropyl 1,4-dihydro-2,6-dimethyl-4-(3-trifluoromethyl-phenyl)-pyridine-3,5-dicarboxylate, di-tert.-butyl 1,4-dihydro-2,6-dimethyl-4-(2-methoxy-phenyl)-pyridine-3,5-dicarboxylate, dicyclopentyl 1,4-dihydro-2,6-dimethyl-4-(3-methylphenyl)-pyridine-3,5-dicarboxylate, Le A 21 974 ~ Z5~ 0 l~
. ~
diallyl 1,4-d;hydro-2,6-d;methyl-4-t3-cyanophenyl)-pyri-dine-3,5-dicarboxylate, dimethyl 1,4-dihydro-2,6-dimethyl-4-(3,4-dioxymethylene-phenyl)-pyridine-3,5-dicarboxylate, dibenzyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5 d;carboxylate, bis-(2-methoxyethyl) 1,4-dihydro-2,6-dimethyl-4-(Z-tri-fluoromethoxyphenyl)-pyrid;ne-3,5-dicarboxylate, bis-(2-phenoxyethyl) 1,4-dihydro-2,6-dimethyl-4-(2-fluoro-phenyl)-pyridine-3,5-dicarboxylate, dimethyl 1,4-dihydro-2,6-diethyl-4-(3-fluorophenyl)-pyri-dene-3,5-dicarboxylate, bis-(2-phenylthioethyl) 1,4-dihydro-2,6-dimethyl-4-(2,3-dimethylphenyl) pyridine-3,5-dicarboxylate, b;s-~pyridyl-2-methyl) 1,4-d;hydro-2,6-d;methyl-4-(2,3-d;chlorophenyl)-pyridine-3,5-d;carboxylate, bis-(2-dimethylam;noethyl) 1,4-d;hydro-2,6-d;methyl-4-(2-methoxyphenyl)-pyr;d;ne-3,5-dicarboxylate, b;s-~2-(N-benzyl-N-methylam;no~-ethyl] 1,4-dihydro-2,6-dimethyl-~-(2-chlorophenyl)-pyr;d;ne-3,5-d;carboxylate, dimethyl 1,4-dihydro-2,6-dipropyl-4-~2-cyclophenyl)-pyr;-d;ne-3,5-d;carboxylate, isopropyl 3-cyano-1,4-d;hydro-2,6-d;methyl-l~-(3,4-dimeth-oxyphenyl)-pyridine-5-carboxylate, cyclopentyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-t2-fluoro-3-chlorophenyl)-pyr;d;ne-5-carboxylate,
The new 1,2,3,4-tetrahydropyridines are characterized by the general formula I
R O2C ~ ~I) in which X represents the nitrile group or the radical -COOR6, R being defined below, R represents phenyl, naphthyl or pyridyl, the phenyl or naphthyl ring being optionally substituted by 1 or 2 identical or different substituents from the group consisting of phenyl, straight-chain or branched alkyl having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, tri-tetra-and pentamethylene, dioxamethylene, halogen, -trifluoromethyl, trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy and cyano, R2 represents a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 20 carbon atoms, which is optionally interrupted by one oxygen or sulphur atom in the chain and/or which is optionally substituted by halogen, cyano, hydroxyl, ~,-,~- or ~-pyridyl, phenyl, phenoxy or phenylthio, it being possible for the phenyl groups to be substituted by halogen, cyano, dialkylamino having 1 to 4 carbon atoms in each alkyl radical, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, trifluoromethyl l~S~O
or trifluoromethoxy, or by an amino group which in turn is sub-stituted by two identical or different substituents from the group consisting of alkyl having 1 to 4 carbon atoms, phenyl or benzyl, R3 and R5, which are identical or different, each repre-sent hydrogen, a straight-chain or branched alkyl radical having up to 4 carbon atoms, a phenyl radical or a benzyl radical, and R4 represents hydrogen, a straight-chain or branched alkyl radical having up to 4 carbon atoms which is optionally interrupted by an oxygen atom, a phenyl radical or a benzyl radical, Rb, when present, is as defined for R~andmaybe the same as or different from R , or a salt thereof with a physiologically tolerated acid, and their salts with physiologically tolerated acids.
Furthermore, it has been found that the compounds of the formula (I) according to the invention are obtained when dihydropyridine compounds of the formula (II) I R
R O2C ~ ~ X
~ [) R Y \ N~ R5 in which R , R2, R3, R , R5 and X have the abovementioned meaning, are electrochemically reduced at a cathode in the presence of a suitable electrolyte system.
In the case where R4 in formula (I) denotes hydrogen, it is also possible to use, as the starting material for the electrochemical reduction, the pyrdine derivatives of the '7(;~
- 2a - 23189-5610 formula ( III ), Rl R O2C ~ X
l ~ I I I ) R3~ ~ N~ ~ R5 -` lZS;~'7~3 ;n which the substituents R1, R2, R3, R5 and X have the abovementioned mean;ng.
The 1,2,3,4-tetrahydropyridine derivat;ves accord-ing to the invention have valuable pharmacological pro-perties. Because of their effect on the circulation, they can be used as antihypertensive agents, as peri-pheral and cerebral vasodilators and as coronary thera-peutic agents and thus are to be regarded as an enrich-ment of pharmacy.
Depending on the nature of the starting materialsused, the preparation of the compounds according to the invention can be represented by the following react;on schemes in which dimethyl 2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate may be chosen as an example:
H ~ CO ~ C ~ CO~ CH~ 2el3~ 2H~H ~ CO~ C ~ CO ~ CH
Hg- cathode H3 C N CH, El, C H C~I, B) H3CO2C~ ¢ ~ CO2CH3 4e~,4H~H,CO2C ~ CO2CH3 N Hg-cathode N ~
H3C CH, H3C H CH3 According to process A, a 1,4-dihydropyridine derivative of the general formula (II) Le_A 21 974 4 l~s~'~L7~3 23l8g-56l0 3 J`~ S R3 X` II~RS
(II) (I~
is converted on a mercury cathode in a suitable electrolyte system into a 1,2,3,4-tetrahydropyridine derivative of the formula (I) according to the invention.
Compounds of the general formula (I) are of particular interest in which R1 represents phenyl or pyridyl, the phenyl ring optionally being substituted by one or two identical or different substituents from the group comprising fluorine, chlorine, cyano, trifluoro-methyl, trifluoromethoxy, alkyl having 1 to 4 C atoms, alkoxy having 1 to 2 C atoms t tetramethylene or phenyl, R2 represents a straiyht-chain or branched cyclic alkyl or alkenyl radical having up to 12 carbon atoms which is optionally interrupted by an oxy-1~5~
gen atom ;n the cha;n and/or wh;ch ;s opt;onally subst;tuted by ~luorine, chlorine, cyano, hydroxyl, phenyl, phenoxy or an am;no group which in turn ;s subst;tuted by two ;dentical or different sub-stituents from the group comprising alkyl hav;ng 1 to 4 C atoms or benzyl, R3 and R5 are ident;cal or d;fferent and each re-present alkyl hav;ng 1 to 2 C atoms, R4 represents hydrogen, alkyl having 1 to 4 C
atoms or benzyl and X represents the nitrile group or represents the radical -C02R6, R6 having the mean;ng of R2 and be;n~ identical to or different from R2.
The derivatives of the general formulae (II) and (III~ used as start;ng materials are known from the lit-erature or can be prepared by methods known from the literature tcompare, for example, U. Eisner and J. Kuthan, Chem. Rev. 72, 1 (1972); E. Wehinger, F. Bossert, G.
Franckowiak and H. Meyer, German Offenlegungsschr;ft (6erman Publ;shed Specification) 2,658,804, publication date: 6.7.1978).
The following may be mentioned as examples:
diethyl 1,4-dihydro-2,6-dimethyl-4-(3-chlorophenyl)-pyri-dine-3,5-dicarboxylate, d;-(n~-butyl 1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine 3,5-dicarboxylate, dihexyl 1,4-d;hydro-2,6-dimethyl-4-(2-chlorophenyl)-pyr;
dine-3,5-dicarboxylate, didecyl 1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)~pyri-dine-3,5-dicarboxylate, diisopropyl 1,4-dihydro-2,6-dimethyl-4-(3-trifluoromethyl-phenyl)-pyridine-3,5-dicarboxylate, di-tert.-butyl 1,4-dihydro-2,6-dimethyl-4-(2-methoxy-phenyl)-pyridine-3,5-dicarboxylate, dicyclopentyl 1,4-dihydro-2,6-dimethyl-4-(3-methylphenyl)-pyridine-3,5-dicarboxylate, Le A 21 974 ~ Z5~ 0 l~
. ~
diallyl 1,4-d;hydro-2,6-d;methyl-4-t3-cyanophenyl)-pyri-dine-3,5-dicarboxylate, dimethyl 1,4-dihydro-2,6-dimethyl-4-(3,4-dioxymethylene-phenyl)-pyridine-3,5-dicarboxylate, dibenzyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5 d;carboxylate, bis-(2-methoxyethyl) 1,4-dihydro-2,6-dimethyl-4-(Z-tri-fluoromethoxyphenyl)-pyrid;ne-3,5-dicarboxylate, bis-(2-phenoxyethyl) 1,4-dihydro-2,6-dimethyl-4-(2-fluoro-phenyl)-pyridine-3,5-dicarboxylate, dimethyl 1,4-dihydro-2,6-diethyl-4-(3-fluorophenyl)-pyri-dene-3,5-dicarboxylate, bis-(2-phenylthioethyl) 1,4-dihydro-2,6-dimethyl-4-(2,3-dimethylphenyl) pyridine-3,5-dicarboxylate, b;s-~pyridyl-2-methyl) 1,4-d;hydro-2,6-d;methyl-4-(2,3-d;chlorophenyl)-pyridine-3,5-d;carboxylate, bis-(2-dimethylam;noethyl) 1,4-d;hydro-2,6-d;methyl-4-(2-methoxyphenyl)-pyr;d;ne-3,5-dicarboxylate, b;s-~2-(N-benzyl-N-methylam;no~-ethyl] 1,4-dihydro-2,6-dimethyl-~-(2-chlorophenyl)-pyr;d;ne-3,5-d;carboxylate, dimethyl 1,4-dihydro-2,6-dipropyl-4-~2-cyclophenyl)-pyr;-d;ne-3,5-d;carboxylate, isopropyl 3-cyano-1,4-d;hydro-2,6-d;methyl-l~-(3,4-dimeth-oxyphenyl)-pyridine-5-carboxylate, cyclopentyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-t2-fluoro-3-chlorophenyl)-pyr;d;ne-5-carboxylate,
2-phenoxyethyl 3-cyano-1,4-d;hydro-2,6-d;methyl-4-~2,3-tetramethylenephenyl)-pyridine-5-carboxylate, 2-dimethylaminoethyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-~2-fluorophenyl)-pyridine-5-carboxylate and 2-(N-benzyl-N-methylamino)-ethyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-(2,3-dihlorophenyl)-pyridine-5-carboxylate.
In order to carry out the process according to the invention, a divided electrolysis cell having a con-ventional cathode, ;n particular having a pool of mercuryas the cathode, and a conventional anode, in particular a Le A ?1 974 ~, sheet of platinum or graphite as the anode, ;s preferably used (compare, for example, N.L. We;nberg, Techn;que of Electroorgan;c Synthesis, Part I, John Wiley & Sons, (1974)).
Prot;c solvents, such as water, methanol, ethanol or mixtures of these, are pr;mar;ly su;table as the reac-tion medium. In add;tion, aprot;c solvents, such as ace-tonitrile or dimethylformam;de, can also be employed w;th advantage when they are d;luted w;th water or another proton donor.
Alkal; metal or tetralkylanlmon;um salts have been found part;cularly su;table as conducting salts, l;th;um tetrafluoroborate, tetraethylammonium tetrafluoroborate or tetrabutylammonium chlor;de be;ng mentioned as pre-ferred examples.
The react;on ;s preferably carr;ed out under anatmosphere of inert gas, such as, For example, nitrogen or a noble gas.
The reaction temperature can be var;ed widely, but the range of 0-50~, ;n particular 10 to 30C, has proved to be particularly advantageous~
The reaction can be carried out both galvano-stat;cally and potentiostat;cally. In the potent;ostat;c embodiment, depending on the substrate, electrolys;s ;s carr;ed on at a cathode potential of about -1.8 to -2.5 V
~measured aga;nst a saturated calomel electrode) until the current approaches zero or until the required amount of charge (2 faraday per mol of 1,4-d;hydropyrid;ne of the formula (II~) has flowed through the circuit. The catholyte ;s then evaporated ;n vacuo, the conduct;ng salt ;s removed by the convent;onal methods of work-up and the substance accord;ng to the ;nvent;on is pur;fied.
When R4 ;n the formula (I) denotes hydrogen, ;t ;s also poss;ble to use, in process var;ant B, the pyr;-d;ne derivatives of the general formula (III), ;n whichthe subst;tuents R1, R2, R3, R5 and X have the abovemen-Le A 21 974 '7(~
,~
tioned meaning, as the su'ostrate of the electrochemical reduction.
Process variant B is carried out entirely in ana-logy to process variant A with the only difference that, according to its nature, 4 faraday-equivalents are neces-sary per mol of pyridine derivative.
Every modificat;on of th;s process, especially changes in the electrolyte system in respect of nature, quantitative composition of the components and pH, can be used in the same manner for the preparation of the com-pounds according to the invention.
Depending on the nature of the radicals R1 to R5 and X, the compounds according to the invention contain at least 3 centres of asymmetry and can thus occur ;n several stereoisomer;c forms. The present invention relates to both the antipodes and racemic forms as welL
as to the mixtures of diastereiomers. The racemic forms can be separated, as can the diasteriomers, into the homo-geneous stereoisomeric constituents in a known manner (compare, for example, E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw ~lill, (1962)).
Apart from the preparation examples listed below, the following acti~e compounds according to the invention may be mentioned:
diethyl 2,6-dimethyl-4-~2-trifluoromethylphenyl)-1,2,3,4-tetrahydropyridine-3~5-dicarboxylate, dibutyl 2,6-dimethyl-4-~2-trifluoromethylphenyl)-192,3,4-tetrahydropyridine-3,5-dicarboxylate, didecyl 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,2,3~4-tetrahydropyridine-3,5-dicarboxylate, diisopropyl 2,6-dimethyl-4-~2-chlorophenyl)-1,2,3,4-tetra-hydropyridine-3,5-dicarboxylate, dicyclopentyl 2,6-dimethyl-4-(2,3-~ichlorophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate~
diallyl 2,6-dimethyl-4-(2-methoxyphenyl)-1,2,3,4-tetra-hydropyr;d;ne-3,5-d;carboxylate, Le A 21 974 ~ ~Z~;~4'~0 ~$~ 9 dibenzyl 2,6-dimethyl-4-t3-methylphenyl~-1,2,3,4-tetra-hydropyridine-3,5-d;carboxylate, bis-(2-methoxyethyl) 2,6-dimethyl-4-(2-trifluoromethoxy-phenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate, bis-(2-phenoxyethyl) 2,6-dimethyl-4-(2-fluoro-3-chloro-phenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate, dimethyl 2,6-diethyl-4-(3-chlorophenyl)-1,2,3,4-tetra-hydropyridine-3,5-dicarboxylate, d;ethyl 2,6-diethyl-4-(2-chlorophenyl)-1,2,3,4-tetra-hydropyridine-3,5-dicarboxylate, 5-ethyl 3-methyl 2,6-dimethyl-4~(2,3-d;chlorophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate,
In order to carry out the process according to the invention, a divided electrolysis cell having a con-ventional cathode, ;n particular having a pool of mercuryas the cathode, and a conventional anode, in particular a Le A ?1 974 ~, sheet of platinum or graphite as the anode, ;s preferably used (compare, for example, N.L. We;nberg, Techn;que of Electroorgan;c Synthesis, Part I, John Wiley & Sons, (1974)).
Prot;c solvents, such as water, methanol, ethanol or mixtures of these, are pr;mar;ly su;table as the reac-tion medium. In add;tion, aprot;c solvents, such as ace-tonitrile or dimethylformam;de, can also be employed w;th advantage when they are d;luted w;th water or another proton donor.
Alkal; metal or tetralkylanlmon;um salts have been found part;cularly su;table as conducting salts, l;th;um tetrafluoroborate, tetraethylammonium tetrafluoroborate or tetrabutylammonium chlor;de be;ng mentioned as pre-ferred examples.
The react;on ;s preferably carr;ed out under anatmosphere of inert gas, such as, For example, nitrogen or a noble gas.
The reaction temperature can be var;ed widely, but the range of 0-50~, ;n particular 10 to 30C, has proved to be particularly advantageous~
The reaction can be carried out both galvano-stat;cally and potentiostat;cally. In the potent;ostat;c embodiment, depending on the substrate, electrolys;s ;s carr;ed on at a cathode potential of about -1.8 to -2.5 V
~measured aga;nst a saturated calomel electrode) until the current approaches zero or until the required amount of charge (2 faraday per mol of 1,4-d;hydropyrid;ne of the formula (II~) has flowed through the circuit. The catholyte ;s then evaporated ;n vacuo, the conduct;ng salt ;s removed by the convent;onal methods of work-up and the substance accord;ng to the ;nvent;on is pur;fied.
When R4 ;n the formula (I) denotes hydrogen, ;t ;s also poss;ble to use, in process var;ant B, the pyr;-d;ne derivatives of the general formula (III), ;n whichthe subst;tuents R1, R2, R3, R5 and X have the abovemen-Le A 21 974 '7(~
,~
tioned meaning, as the su'ostrate of the electrochemical reduction.
Process variant B is carried out entirely in ana-logy to process variant A with the only difference that, according to its nature, 4 faraday-equivalents are neces-sary per mol of pyridine derivative.
Every modificat;on of th;s process, especially changes in the electrolyte system in respect of nature, quantitative composition of the components and pH, can be used in the same manner for the preparation of the com-pounds according to the invention.
Depending on the nature of the radicals R1 to R5 and X, the compounds according to the invention contain at least 3 centres of asymmetry and can thus occur ;n several stereoisomer;c forms. The present invention relates to both the antipodes and racemic forms as welL
as to the mixtures of diastereiomers. The racemic forms can be separated, as can the diasteriomers, into the homo-geneous stereoisomeric constituents in a known manner (compare, for example, E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw ~lill, (1962)).
Apart from the preparation examples listed below, the following acti~e compounds according to the invention may be mentioned:
diethyl 2,6-dimethyl-4-~2-trifluoromethylphenyl)-1,2,3,4-tetrahydropyridine-3~5-dicarboxylate, dibutyl 2,6-dimethyl-4-~2-trifluoromethylphenyl)-192,3,4-tetrahydropyridine-3,5-dicarboxylate, didecyl 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,2,3~4-tetrahydropyridine-3,5-dicarboxylate, diisopropyl 2,6-dimethyl-4-~2-chlorophenyl)-1,2,3,4-tetra-hydropyridine-3,5-dicarboxylate, dicyclopentyl 2,6-dimethyl-4-(2,3-~ichlorophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate~
diallyl 2,6-dimethyl-4-(2-methoxyphenyl)-1,2,3,4-tetra-hydropyr;d;ne-3,5-d;carboxylate, Le A 21 974 ~ ~Z~;~4'~0 ~$~ 9 dibenzyl 2,6-dimethyl-4-t3-methylphenyl~-1,2,3,4-tetra-hydropyridine-3,5-d;carboxylate, bis-(2-methoxyethyl) 2,6-dimethyl-4-(2-trifluoromethoxy-phenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate, bis-(2-phenoxyethyl) 2,6-dimethyl-4-(2-fluoro-3-chloro-phenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate, dimethyl 2,6-diethyl-4-(3-chlorophenyl)-1,2,3,4-tetra-hydropyridine-3,5-dicarboxylate, d;ethyl 2,6-diethyl-4-(2-chlorophenyl)-1,2,3,4-tetra-hydropyridine-3,5-dicarboxylate, 5-ethyl 3-methyl 2,6-dimethyl-4~(2,3-d;chlorophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate,
3-ethyl 5-methyl 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,2~3,4-tetrahydropyridine-3~5-dicarboxylate, 15 5-isopropyl 3-methyl 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate, 5-(2-(N-benzyl-N-methylamino)-ethyl) ~-methyl 2,6-dimethyl-
4-(2-chloroohenyl)-1,2,3,4-tetrahydropyridine-3,5-dicar-boxylate and 20 5-isopropyl 3-t2-methoxyethyl) 2,6-dimethyl 4-(2-chloro-3-methoxyphenyl)-1,2,3,4-tetrahydropyr;dine-3,5-dicarbox-ylate.
The new compounds have a broad and versat;le spec-trum of pharmacological activity.
In detail, the following main effects have been demonstrated in animal experiments:
1. On parenteral, oral and perlingual administration, the compounds bring about a marked and long-lasting dila tation of the coronary vessels. This effect on the coro-nary vessels is potentiated by a simultaneous cardiac-relieving effect resembl;ng nitrites.
They affect or change the cardiac metabolism in the sense of saving energy.
2. The excitability of the impulse-forming and con-duct;on systems with;n the heart ;s decreased so that adetectable antifibrillatory activity results at thera-Le A 21 974 _ ~zs~
peutic doses.
3. The tone of the smooth muscle of the vessels ;s greatly decreased under the action of the compounds. Th;s vasospasmolyt;c effect can take place in the entire vascu-; 5 lar system or can manifest itself in a manner more or less isolated in restricted vascular regions ~such as, for example, the central nervous system). Thus the compounds are part;cularly suitable as cerebral therapeutic agents.
4. Compounds lower the blood pressure of normo-tensive and hypertensive animals and can thus be used as antihypertensive agents.
The new compounds have a broad and versat;le spec-trum of pharmacological activity.
In detail, the following main effects have been demonstrated in animal experiments:
1. On parenteral, oral and perlingual administration, the compounds bring about a marked and long-lasting dila tation of the coronary vessels. This effect on the coro-nary vessels is potentiated by a simultaneous cardiac-relieving effect resembl;ng nitrites.
They affect or change the cardiac metabolism in the sense of saving energy.
2. The excitability of the impulse-forming and con-duct;on systems with;n the heart ;s decreased so that adetectable antifibrillatory activity results at thera-Le A 21 974 _ ~zs~
peutic doses.
3. The tone of the smooth muscle of the vessels ;s greatly decreased under the action of the compounds. Th;s vasospasmolyt;c effect can take place in the entire vascu-; 5 lar system or can manifest itself in a manner more or less isolated in restricted vascular regions ~such as, for example, the central nervous system). Thus the compounds are part;cularly suitable as cerebral therapeutic agents.
4. Compounds lower the blood pressure of normo-tensive and hypertensive animals and can thus be used as antihypertensive agents.
5. Com-poundls ha;ve strong myospasmolytic effects which are marked on the smooth muscle of the stomach, intestinal tract, urogenital tract and respiratory tract.
Due to these properties, the compounds according to the invention are particularly suitable for the pro-phylaxis and therapy of acute and chronic ischaem;c heart disease in its widest meaning, for the therapy of hyper-tension and for the treatment of disturbances of cerebral ~0 and peripheral blood flow.
The new active compounds can be converted in a known manner into the convent;onal formulations, such as tablets, capsules, coated tablets, pills, granules~ aero-sols, syrups, emulsions, suspensions and solutions, us;ng inert, non-toxic, pharmaceutically suitable veh;cles or salts. The therapeutically active compounds should ;n each case be present in a concentration of about 0.5 to 90X by we;ght of the total m;xture, that ;s to say ;n amounts which suffice to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the act;ve compounds w;th solvents and/or veh;cles, optionally with the use of emuls;f;ers and/or dispers;ng agents and, for example, when using water as a d;luent, organic solvents can opt;onally be used as auxiliary solvents.
Le A 21 974 ~S~ ~'7~
,....
,1.~, //
,~
Examples of aux;l;aries wh;ch may be mentioned are:
Water, non-toxic organic solvents, such as paraff;ns (for example petroleum fract;ons), vegetable o;ls (for example groundnut oil/sesame oil), alcohols (for example ethyl alcohol and glycerol), gLycols (for example propylene glycol and polyethylene glycol), solid vehicles, such as, for example, natural rock powders ~for example kaolins, aluminas, talc and chalk), synthetic rock powders (for example highly disperse silica and silicates), sugars (for example crude sugar, lactose and glucose), emulsi-fiers (for example polyoxyethylene-fatty ac;d esters, polyoxyethylene-fatty alcohol ethers, alkyl sulphonates and aryl sulphonates), dispersing agents (for example l;gnin, sulphite waste liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants tfor example-magnes;um stearate, talc, stearic acid and sodium lauryl sulphate).
Administration ;s effected in the customary m~anner, preferably orally or parenterally, in part;cular perlin-gually or intravenously. In the case of oral adm;nistra-tion, the tablets can, of course, also contain, in add;-tion to the vehicles mentioned, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, to-gether with various add;tional substances, such as starch,preferably potato starch, gelatine and the like. Further-more, lubricants such as magnesium stearate, sodium lauryl sulphate and talc can be co-used when making tablets. In the case of aqueous suspensions and/or elixirs wh;ch are intended for oral use, the active compounds can be m;xed with various flavour-improving agents or colorants ;n add;tion to the abovementioned auxiliaries.
In the case of parenteral administration, solu-tions of the active compounds, employing suitable l;qu;d veh;cles, can be used.
In general, it has proved advantageous, in the Le A 21 97~
~ZS~417~
case of ;ntravenous administration, to administer amounts of abo~t n.001 to 10 mg/kg, preferably O.OS to 5 mg/kg, of body weight da;ly to achieve effective results and, in the case of oral administration, the dosage is about 0.05 to 20 mg/kg, preferably 0.5 to S mg/kg of body weight daily.
Nevertheless, it can at times be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight of the experimental animal or of the nature of the administration method, but also because of the species of animal and its individual beha-viour towards the medicament, or the nature of the for-mulation of the medicament and the time or interval over which the administration takes place. Thus it can suffice in some cases to manage with less than the abovementioned minimum amount, whilst in other cases the upper limit men-tioned must be exceeded~
Where relatively large amounts are admin;stered, it can be advisable to div;de these ;nto several ;nd;v;-dual adm;n;strations over the course of the day. The same dosage range is envisaged for administration in human ; medicine. In this connection, the above statement-s sim;-larly apply.
Preparat;on examples Example 1 Dimethyl 2,6-d;methyl-4-phenyl-1,2,3,4-tetrahydropyri-dine 3,5-dicarboxylate `h H3C ' CH3 H
5 g ~17 mmols) of dimethyl 1,4 d;hydro-2,6-d;-methyl-4-phenylpyridine-3,5-dicarboxylate ;n 170 ml of a 0.1 molar solution of tetraethylammonium tetrafluoroborate in methanol were electrolysed in a divided electrolysis Le A 21 974 ~2S~7~3 ,. ..
cell (see N.L. Weinberg, Technique of Electroorganic Synthesis, Part I, John Wiley ~ Sons, t19743) having a mercury cathode and a plat;num sheet anode at a cathode potential of -2.0 V (aga;nst a saturated calomel electrode (SCE)), at 25C and under a nitrogen atmosphere. The same supporting electrolyte was used for the cathode and anode chambers.
After an amount of charge of 3,300 coulomb ~34 mmol e ~- 2 faraday equivalents) had flowed through, the current approached ~ero. The anolyte was discarded and the catholyte was evaporated in vacuo after separating off the mercury. The residue was taken up in dichloro-methane, the organic phase was washed several times with water and, after drying over anhydrous sodium sulphate, was distilled under reduced pressure. The remaining oil solidif;ed on triturat;on w;th ether, it was f;ltered off with suct;on and recrystallised from methanol.
Melt;ng point: 165-167C, y;eld: 2 g (39%).
Example 2 Cl H,CO2C ~ ~ CO2CH3 H,C H CEI 3 In analogy to Example 1, dimethyl 2,6-dimethyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydropyrid;ne-3,5-d;car-boxylate was obta;ned by cathodic reduction of d;methyl 1,4-d;hydro-2,6-dimethyl-4-(2-chlorophenyl)-pyrid;ne-3,5-dicarboxylate ;n methanol/tetraethylammonium tetra-fluoroborate, melt;ng po;nt: 12~-130C, yield: 54%.
Le A 21 974 l~S~4~
. ,,,' Example 3 ~3 H3CO2C ~¢XCO2CE~3 ~3 C H CH, In analogy to Example 1~ dimethyl 2,6-d;methyl-4-~4-chlorophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarbox-ylate was obtained by reduction of dimethyl 1,4-dihydro-2,6-d;methyl-4-~4-chlorophenyl)-pyridine~3,5-dicarboxy-late at a mercury cathode in methanol/tetraethylammonium tetrafluoroborate, melt;ng point: 186-188C, y;eld: 62%.
Example 4 ~C~, ~3CO2C ~ ~ C02CX3 H3C ~ C~3 In analogy to Example 1~ d;methyl 2,6-dimethyl 4-; (2-methylphenyl)-1,203,4-tetrahydropyridine-3,5-dicarboxy-late was obtained by reduction of dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-methylphenyl?-pyridine-3,5-dicarboxy-late at a mercury cathode in methanol/tetraethylammonium tetrafluoroborate, melting point: 125-127C, yield: 53%.
Exa~ple 5 tl ~ CO~ C ~ C02 C~3 H3C H C~, In analogy to Example 1, dimethyl 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,2,3,4-tetrahydropyr;d;ne-3,5-d;carboxylate was obta;ned by cathod;c reduct;on of Le ~ 21 974 lZ5~
,, dimethyl 1,4-d;hydro-2,6-d;methyl-4-(2-trifluoromethyl-phenyl)-pyr;dine-3,5~dicarboxylate at a mercury electrode in methanol/tetraethylammonium tetrafluoroborate, melting point 178-181C, yield: 62% of theory.
Example 6 OCH, H3CO2C~ XCO2C~3 H3 C H CH, In analogy to Example 1~ dimethyl 2,6-dimethyl-4-(2-methoxyphenyl)-1,2,3,4-tetrahydropyridine-3,5-di-: carboxylate was obta;ned by reduction of dimethyl 1,4-dihydro-2,6-dimethyl-4-~2-methoxyphenyl)-pyridine-3,5-dicarboxylate at a mercury cathode in methanol/tetraethyl-ammonium tetrafluoroborate, melting point: 197-199C, yield: 67Z.
Example 7 ~ CN
H~CO~C ~ CO2C~3 H,C H CH, In analogy to Example 1, dimethyl 2,6-dimethyl-4-~3-cyanophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxy-late was obtained by reduction of dimethyl 1,4-d;hydro-2,6-dimethyl-4-~3-cyanophenyl)-pyridine-3,5-dicarboxylate at a mercury cathode in methanol/tetraethylammonium tetra-fluoroborate, melting point: 170-173C~ yield: 35XA
Le A 21 974 lZ~ ;JO
ExaMple 8 ~ OCF~
H,CO,C ~ COlCH3 H3C H CH, In analogy to Exam~ple 1, dimethyl 2,6-dimethyl-4-(2-tr1fluoromethoxyphenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate was obtained by reduction of dimethyl ~ dihydro-2,6-dimethyl-4-(2-trifluoromethoxyphenyl)-pyridine-3,5-dicarboxylate at a mercury cathode in meth-anol/tetraethylammonium tetrafluoroborate, melting point:
145C, y;eld: 32%~
Example 9 Cl ~ C~I
H~CO2C ~[ ~ CO2 C~3 N
H.3 C ~ C~, In analogy to Example 1, d;methyl 2,6-dimethyl-4-(2,3-dichlorophenyl)-1~2,3,4-tetrahydropyridine-3,5-dicarboxylate was obta;ned by reduction of dimethyl 1,4 d;hydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate at a mercury cathode in methanol/tetraethyl-ammonium tetrafluoroborate, melting point: 170-172C, yield: 64%.
Example 10 ~ C1 F
~,CO2C ~ ~ CO2Ca3 ~C H C~3 In analogy to Example 1, dimethyl 2,6-dimethyl-Le A 21 974 - ~s~
4-(2-fluoro 3~chlorophenyl)-1,2,3,4-tetrahydropyr;d;ne-3,5-d;carboxylate was obta;ned by Gathod;c reduct;on of d;methyl 1,4-d;hydro-2,6-d;methyl 4-(2-fluoro-3-chloro-phenyl)-pyr;d;ne-3,5-d;carboxylate at a mercury electrode ;n methanol/tetraethylammon;um tetrafluoroborate, melt;ng po;nt: 172-174C, y;eld: 38~.
Example 11 H~ CO~ C `~NX C2 CH3 H3 C ~ CE~3 C~i3 In analogy to Example 1~ d;methyl 1,2,6-tr;methyl-4-phenyl-1~2,3,4-tetrahydropyr;d;ne-3,5-d;carboxylate was obta;ned by reduction of dimethyl 1,4-dihydro-1,2,6-tri-methyl-4-phenylpyridine-3,5-dicarboxylate at a mercury cathode ;n methanol/tetraethylammon;um tetrafluoroborate, melt;ng point: 89-90C, yield: 29%.
Example 12 ~:1 H, C02 C ~X C~l H~C N C~
In analogy to Example 1, methyl 3-cyano-2,6-di-methyl-4-phenyl-1,2,3,4-tetrahydropyrid;ne-5-carboxylate was obta;ned by reduct;on of methyl 3-cyano-1,4-d;hydro-2,6-d;methyl-4-phenylpyr;d;ne-5-carboxylate at a mercury cathode ;n methanol/tetraethylammon;um tetrafluoroborate, melt;ng po;nt: 170-172C, y;eld: 45%.
Le A 21 974 ~ZS~'7~
. . ~, Example 13 [~Cl H 3 CO 2 C ~X CN
In analogy to Example 1~ methyl 3-cyano-2,6-d;-methyl-4-~2-chlorophenyl)-1,2,3,4-tetrahydropyrid;ne-5-carboxylate was obta;ned by reduction of methyl 3-cyano-1,4-d;hydro-2~6-d;methyl-4-(2-chlorophenyl)-pyr;d;ne-5-carboxylate at a mercury cathode ;n methanol/tetrabutyl-ammon;um tetrafluoroborate, melt;ng po;nt: 168-170C, y;eld: 71%~
Example 14 1~ 11 ~ CH3 H, CO2 C ~ CN
H;,C H C~3 In analogy to Example 1, methyl 3-cyano-2,6-d;-methyl-4-(2-methylphenyl)-1,2,3,4-tetrahydropyrid;ne-5-carboxylate was obta;ned by cathodic reduct;on of methyl 3-cyano-1,4-d;hydro-2,6-d;methyl-4-(2-methylphenyl)-pyr;-d;ne-S-carboxylate at a mercury electrode ;n methanol/
: l;th;um tetrafluoroborate, melt;ng po;nt: 194-196C, y;eld: 53%.
Example 15 ~
~ CF, H,CO 2 C~ "-~CN
ll l H3C H CH, In analogy to Example 1, methyl 3-cyano-2,6-di-Le A 21 974 ~;~S'~4'~
, ~
methyl-4-(2-trifluoromethylphenyl)-1,2,3,4-tetrahydro-pyridine-5-carboxylate was obtained by cathodic reduction of methyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-(2-trifluoro-methylphenyl)-pyr;dine-5-carboxylate at a mercury elec-trode in aqueous methanol/tetraethylammonium tetrafluoro-borate, melting point: 202-204C, yield: 59%.
Example 16 ~ C1 H5C~O2C ~ CN
H,C ~ C~3 In analogy to Example 1, ethyl 3-cyano-2,6-di-methyl-4-t2-chlorophenyl)-1,2,3,4-tetrahydropyrid;ne-5-carboxylate was obtained by cathodic reduction of ethyl 3`-cyano-1,4-d;hydro-2,6-dimethyl-4-(2-chlorophenyl)-pyri-dine-5-carboxylate ;n ethanol/tetraethylammonium tetra-fluoroborate, melting po;nt: 184-186C, yield: 60%.
Example 17 ~1~ Cl Hs Cl 0, C ~ CN
C~, In analogy to Example 1, ethyl 3-cyano-1,2,6~tri-methyl-4-(2-chlorophenyl~-1,2,3,4-tetrahydropyridine-5-carboxylate was obtained by cathodic reduction of ethyl 3-cyano-1,4-dihydro-1,2,6-trimethyl-4-~2-chlorophenyl)-pyridine-5-carboxylate at a mercury electrode in methanol/
tetraethylammonium tetrafluoroborate, melting point:
147-148C, yield: 30%.
Le A 21 974 v -- ,21' --Example 18 ~ Cl E~2 C=HC-H2 COz C 1 C~!l H,C' N CH3 H
In analogy to Example 1, allyl 3~cyano-2,6-di-methyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydropyridine-5-carboxylate was obtained by reduction of allyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-5-carboxylate at a mercury electrode in methanol/tetraethyl-ammonium tetrafluoroborate, melting point: 158-159C, yield: 35X.
Example 19 f~, ~ Cl HIC-C-O~C ~ CN
C~3 11 1 H,C '~N~ C~3 H
In analogy to Example 1, tert.-butyl 3-cyano-2,6-dimethyl-4-~Z-chlorophenyl)-1,2,3,4-tetrahydropyridine-5-carboxylate was obtained by reduction of tert~-butyl 3-cyano-1,4-d;hydro-2,6-dimethyl-4-(2-chlorophenyl)-pyri-dine-5-carboxylate at a mercury cathode in methanol/tetra-ethylammonium tetrafluoroborate, melting point: Z04-205C, yield: 32%.
~ CF, ~,COH2CH2CO2C ~ CN
H,C N CH, In analogy to Example 1, 2-methoxyethyl 3-cyano-Le A 21 974 , ~."
2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,2,3,4-tetra-hydropyridine-5-carboxylate was obtained by reduction of 2-methoxyethyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-(2-tri-fluoromethylphenyl)-pyridine-5-carboxylate at a mercury cathode in a 1:1 mixture of methanol/acetonitrile/tetra-ethylam~on;um tetrafluoroborate, melting po;rt: 182-183C, yield: 54%.
Example 21 Cl H,CO2C~ ~ CN
11 ~
H3C N'-`CH3 H
In analogy to Example 1, benzyl 3-cyano-2,6-di-methyl-~-t2-chlorophenyl)-1,2,3,4-tetrahydropyridine-5-carboxylate was obtained by cathodic reduction of benzyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyri-dine-5-carboxylate at a mercury electrode in methanol/
tetraethylammonium tetrafluoroborate, melting point:
194-196C, yield: 45~.
H 2 CoH2cH 2 C2 C ~ CN
H,C W C~3 .
In analogy to Example 1, 2-benzyloxyethyl 3-cyano-2,6-dimethyl-4-t2-chlorophenyl)-1,2,3,4-tetrahydropyridine-5-carboxylate was obtained by cathodic reduction of 2-benzy-loxyethyl 3-cyano-1,4-dihydro-2,6-dimethyl--4-(2 chloro-phenyl)-pyridine-5-carboxylate at a mercury electrode ;n methanol/acetonitrile/tetrae~hylammonium tetrafluoro-borate, melting point: 88-90C, yield: 25%.
Le A 21 974 -- ~ZS~Z~'70 I ,~. ' , .
Example 23 ~ Cl NC-H2 CH;I CO, C ~X C~J
H,C N CR}
E~
In analogy to Example 1, 2-cyanoethyl 3-cyano-2,6-dimethyl-4-(2-chlorophenyl)-1,203,4-tetrahydropyri-S dine-5-carboxylate was obtained by reduction of 2-cyano-ethyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-5-carboxylate at a mercury cathode in methaol/
tetraethylammonium tetrafluoroborate, melt;ng po;nt:
189-191C, y;eld: 25X.
Exa.mp~e 2.4 ~ Cl H3C0 2 C ~ CN
~ I
H,C N CH3 H
In analogy to Example 1, methyl 3-cyano-2,6-di-methyl-4-(2,3-d;chlorophenyl~-1,2,3,4-tetrahydropyr;d;ne-5-carboxylate was obta;ned by reduct;on of methyl 3-cyano~
1,4-d;hydro-2,6-d;methyl-4-(2,3-dichlorophenyl)-pyr;dine-5-carboxylate at a mercury cathode in methanol/tetraethyl-ammon;um tetrafluoroborate, melt;ng point: 238-240C~
y;eld: 45X.
2û
Le A 21 974
Due to these properties, the compounds according to the invention are particularly suitable for the pro-phylaxis and therapy of acute and chronic ischaem;c heart disease in its widest meaning, for the therapy of hyper-tension and for the treatment of disturbances of cerebral ~0 and peripheral blood flow.
The new active compounds can be converted in a known manner into the convent;onal formulations, such as tablets, capsules, coated tablets, pills, granules~ aero-sols, syrups, emulsions, suspensions and solutions, us;ng inert, non-toxic, pharmaceutically suitable veh;cles or salts. The therapeutically active compounds should ;n each case be present in a concentration of about 0.5 to 90X by we;ght of the total m;xture, that ;s to say ;n amounts which suffice to achieve the dosage range indicated.
The formulations are prepared, for example, by extending the act;ve compounds w;th solvents and/or veh;cles, optionally with the use of emuls;f;ers and/or dispers;ng agents and, for example, when using water as a d;luent, organic solvents can opt;onally be used as auxiliary solvents.
Le A 21 974 ~S~ ~'7~
,....
,1.~, //
,~
Examples of aux;l;aries wh;ch may be mentioned are:
Water, non-toxic organic solvents, such as paraff;ns (for example petroleum fract;ons), vegetable o;ls (for example groundnut oil/sesame oil), alcohols (for example ethyl alcohol and glycerol), gLycols (for example propylene glycol and polyethylene glycol), solid vehicles, such as, for example, natural rock powders ~for example kaolins, aluminas, talc and chalk), synthetic rock powders (for example highly disperse silica and silicates), sugars (for example crude sugar, lactose and glucose), emulsi-fiers (for example polyoxyethylene-fatty ac;d esters, polyoxyethylene-fatty alcohol ethers, alkyl sulphonates and aryl sulphonates), dispersing agents (for example l;gnin, sulphite waste liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants tfor example-magnes;um stearate, talc, stearic acid and sodium lauryl sulphate).
Administration ;s effected in the customary m~anner, preferably orally or parenterally, in part;cular perlin-gually or intravenously. In the case of oral adm;nistra-tion, the tablets can, of course, also contain, in add;-tion to the vehicles mentioned, additives such as sodium citrate, calcium carbonate and dicalcium phosphate, to-gether with various add;tional substances, such as starch,preferably potato starch, gelatine and the like. Further-more, lubricants such as magnesium stearate, sodium lauryl sulphate and talc can be co-used when making tablets. In the case of aqueous suspensions and/or elixirs wh;ch are intended for oral use, the active compounds can be m;xed with various flavour-improving agents or colorants ;n add;tion to the abovementioned auxiliaries.
In the case of parenteral administration, solu-tions of the active compounds, employing suitable l;qu;d veh;cles, can be used.
In general, it has proved advantageous, in the Le A 21 97~
~ZS~417~
case of ;ntravenous administration, to administer amounts of abo~t n.001 to 10 mg/kg, preferably O.OS to 5 mg/kg, of body weight da;ly to achieve effective results and, in the case of oral administration, the dosage is about 0.05 to 20 mg/kg, preferably 0.5 to S mg/kg of body weight daily.
Nevertheless, it can at times be necessary to deviate from the amounts mentioned, and in particular to do so as a function of the body weight of the experimental animal or of the nature of the administration method, but also because of the species of animal and its individual beha-viour towards the medicament, or the nature of the for-mulation of the medicament and the time or interval over which the administration takes place. Thus it can suffice in some cases to manage with less than the abovementioned minimum amount, whilst in other cases the upper limit men-tioned must be exceeded~
Where relatively large amounts are admin;stered, it can be advisable to div;de these ;nto several ;nd;v;-dual adm;n;strations over the course of the day. The same dosage range is envisaged for administration in human ; medicine. In this connection, the above statement-s sim;-larly apply.
Preparat;on examples Example 1 Dimethyl 2,6-d;methyl-4-phenyl-1,2,3,4-tetrahydropyri-dine 3,5-dicarboxylate `h H3C ' CH3 H
5 g ~17 mmols) of dimethyl 1,4 d;hydro-2,6-d;-methyl-4-phenylpyridine-3,5-dicarboxylate ;n 170 ml of a 0.1 molar solution of tetraethylammonium tetrafluoroborate in methanol were electrolysed in a divided electrolysis Le A 21 974 ~2S~7~3 ,. ..
cell (see N.L. Weinberg, Technique of Electroorganic Synthesis, Part I, John Wiley ~ Sons, t19743) having a mercury cathode and a plat;num sheet anode at a cathode potential of -2.0 V (aga;nst a saturated calomel electrode (SCE)), at 25C and under a nitrogen atmosphere. The same supporting electrolyte was used for the cathode and anode chambers.
After an amount of charge of 3,300 coulomb ~34 mmol e ~- 2 faraday equivalents) had flowed through, the current approached ~ero. The anolyte was discarded and the catholyte was evaporated in vacuo after separating off the mercury. The residue was taken up in dichloro-methane, the organic phase was washed several times with water and, after drying over anhydrous sodium sulphate, was distilled under reduced pressure. The remaining oil solidif;ed on triturat;on w;th ether, it was f;ltered off with suct;on and recrystallised from methanol.
Melt;ng point: 165-167C, y;eld: 2 g (39%).
Example 2 Cl H,CO2C ~ ~ CO2CH3 H,C H CEI 3 In analogy to Example 1, dimethyl 2,6-dimethyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydropyrid;ne-3,5-d;car-boxylate was obta;ned by cathodic reduction of d;methyl 1,4-d;hydro-2,6-dimethyl-4-(2-chlorophenyl)-pyrid;ne-3,5-dicarboxylate ;n methanol/tetraethylammonium tetra-fluoroborate, melt;ng po;nt: 12~-130C, yield: 54%.
Le A 21 974 l~S~4~
. ,,,' Example 3 ~3 H3CO2C ~¢XCO2CE~3 ~3 C H CH, In analogy to Example 1~ dimethyl 2,6-d;methyl-4-~4-chlorophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarbox-ylate was obtained by reduction of dimethyl 1,4-dihydro-2,6-d;methyl-4-~4-chlorophenyl)-pyridine~3,5-dicarboxy-late at a mercury cathode in methanol/tetraethylammonium tetrafluoroborate, melt;ng point: 186-188C, y;eld: 62%.
Example 4 ~C~, ~3CO2C ~ ~ C02CX3 H3C ~ C~3 In analogy to Example 1~ d;methyl 2,6-dimethyl 4-; (2-methylphenyl)-1,203,4-tetrahydropyridine-3,5-dicarboxy-late was obtained by reduction of dimethyl 1,4-dihydro-2,6-dimethyl-4-(2-methylphenyl?-pyridine-3,5-dicarboxy-late at a mercury cathode in methanol/tetraethylammonium tetrafluoroborate, melting point: 125-127C, yield: 53%.
Exa~ple 5 tl ~ CO~ C ~ C02 C~3 H3C H C~, In analogy to Example 1, dimethyl 2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,2,3,4-tetrahydropyr;d;ne-3,5-d;carboxylate was obta;ned by cathod;c reduct;on of Le ~ 21 974 lZ5~
,, dimethyl 1,4-d;hydro-2,6-d;methyl-4-(2-trifluoromethyl-phenyl)-pyr;dine-3,5~dicarboxylate at a mercury electrode in methanol/tetraethylammonium tetrafluoroborate, melting point 178-181C, yield: 62% of theory.
Example 6 OCH, H3CO2C~ XCO2C~3 H3 C H CH, In analogy to Example 1~ dimethyl 2,6-dimethyl-4-(2-methoxyphenyl)-1,2,3,4-tetrahydropyridine-3,5-di-: carboxylate was obta;ned by reduction of dimethyl 1,4-dihydro-2,6-dimethyl-4-~2-methoxyphenyl)-pyridine-3,5-dicarboxylate at a mercury cathode in methanol/tetraethyl-ammonium tetrafluoroborate, melting point: 197-199C, yield: 67Z.
Example 7 ~ CN
H~CO~C ~ CO2C~3 H,C H CH, In analogy to Example 1, dimethyl 2,6-dimethyl-4-~3-cyanophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxy-late was obtained by reduction of dimethyl 1,4-d;hydro-2,6-dimethyl-4-~3-cyanophenyl)-pyridine-3,5-dicarboxylate at a mercury cathode in methanol/tetraethylammonium tetra-fluoroborate, melting point: 170-173C~ yield: 35XA
Le A 21 974 lZ~ ;JO
ExaMple 8 ~ OCF~
H,CO,C ~ COlCH3 H3C H CH, In analogy to Exam~ple 1, dimethyl 2,6-dimethyl-4-(2-tr1fluoromethoxyphenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate was obtained by reduction of dimethyl ~ dihydro-2,6-dimethyl-4-(2-trifluoromethoxyphenyl)-pyridine-3,5-dicarboxylate at a mercury cathode in meth-anol/tetraethylammonium tetrafluoroborate, melting point:
145C, y;eld: 32%~
Example 9 Cl ~ C~I
H~CO2C ~[ ~ CO2 C~3 N
H.3 C ~ C~, In analogy to Example 1, d;methyl 2,6-dimethyl-4-(2,3-dichlorophenyl)-1~2,3,4-tetrahydropyridine-3,5-dicarboxylate was obta;ned by reduction of dimethyl 1,4 d;hydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-pyridine-3,5-dicarboxylate at a mercury cathode in methanol/tetraethyl-ammonium tetrafluoroborate, melting point: 170-172C, yield: 64%.
Example 10 ~ C1 F
~,CO2C ~ ~ CO2Ca3 ~C H C~3 In analogy to Example 1, dimethyl 2,6-dimethyl-Le A 21 974 - ~s~
4-(2-fluoro 3~chlorophenyl)-1,2,3,4-tetrahydropyr;d;ne-3,5-d;carboxylate was obta;ned by Gathod;c reduct;on of d;methyl 1,4-d;hydro-2,6-d;methyl 4-(2-fluoro-3-chloro-phenyl)-pyr;d;ne-3,5-d;carboxylate at a mercury electrode ;n methanol/tetraethylammon;um tetrafluoroborate, melt;ng po;nt: 172-174C, y;eld: 38~.
Example 11 H~ CO~ C `~NX C2 CH3 H3 C ~ CE~3 C~i3 In analogy to Example 1~ d;methyl 1,2,6-tr;methyl-4-phenyl-1~2,3,4-tetrahydropyr;d;ne-3,5-d;carboxylate was obta;ned by reduction of dimethyl 1,4-dihydro-1,2,6-tri-methyl-4-phenylpyridine-3,5-dicarboxylate at a mercury cathode ;n methanol/tetraethylammon;um tetrafluoroborate, melt;ng point: 89-90C, yield: 29%.
Example 12 ~:1 H, C02 C ~X C~l H~C N C~
In analogy to Example 1, methyl 3-cyano-2,6-di-methyl-4-phenyl-1,2,3,4-tetrahydropyrid;ne-5-carboxylate was obta;ned by reduct;on of methyl 3-cyano-1,4-d;hydro-2,6-d;methyl-4-phenylpyr;d;ne-5-carboxylate at a mercury cathode ;n methanol/tetraethylammon;um tetrafluoroborate, melt;ng po;nt: 170-172C, y;eld: 45%.
Le A 21 974 ~ZS~'7~
. . ~, Example 13 [~Cl H 3 CO 2 C ~X CN
In analogy to Example 1~ methyl 3-cyano-2,6-d;-methyl-4-~2-chlorophenyl)-1,2,3,4-tetrahydropyrid;ne-5-carboxylate was obta;ned by reduction of methyl 3-cyano-1,4-d;hydro-2~6-d;methyl-4-(2-chlorophenyl)-pyr;d;ne-5-carboxylate at a mercury cathode ;n methanol/tetrabutyl-ammon;um tetrafluoroborate, melt;ng po;nt: 168-170C, y;eld: 71%~
Example 14 1~ 11 ~ CH3 H, CO2 C ~ CN
H;,C H C~3 In analogy to Example 1, methyl 3-cyano-2,6-d;-methyl-4-(2-methylphenyl)-1,2,3,4-tetrahydropyrid;ne-5-carboxylate was obta;ned by cathodic reduct;on of methyl 3-cyano-1,4-d;hydro-2,6-d;methyl-4-(2-methylphenyl)-pyr;-d;ne-S-carboxylate at a mercury electrode ;n methanol/
: l;th;um tetrafluoroborate, melt;ng po;nt: 194-196C, y;eld: 53%.
Example 15 ~
~ CF, H,CO 2 C~ "-~CN
ll l H3C H CH, In analogy to Example 1, methyl 3-cyano-2,6-di-Le A 21 974 ~;~S'~4'~
, ~
methyl-4-(2-trifluoromethylphenyl)-1,2,3,4-tetrahydro-pyridine-5-carboxylate was obtained by cathodic reduction of methyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-(2-trifluoro-methylphenyl)-pyr;dine-5-carboxylate at a mercury elec-trode in aqueous methanol/tetraethylammonium tetrafluoro-borate, melting point: 202-204C, yield: 59%.
Example 16 ~ C1 H5C~O2C ~ CN
H,C ~ C~3 In analogy to Example 1, ethyl 3-cyano-2,6-di-methyl-4-t2-chlorophenyl)-1,2,3,4-tetrahydropyrid;ne-5-carboxylate was obtained by cathodic reduction of ethyl 3`-cyano-1,4-d;hydro-2,6-dimethyl-4-(2-chlorophenyl)-pyri-dine-5-carboxylate ;n ethanol/tetraethylammonium tetra-fluoroborate, melting po;nt: 184-186C, yield: 60%.
Example 17 ~1~ Cl Hs Cl 0, C ~ CN
C~, In analogy to Example 1, ethyl 3-cyano-1,2,6~tri-methyl-4-(2-chlorophenyl~-1,2,3,4-tetrahydropyridine-5-carboxylate was obtained by cathodic reduction of ethyl 3-cyano-1,4-dihydro-1,2,6-trimethyl-4-~2-chlorophenyl)-pyridine-5-carboxylate at a mercury electrode in methanol/
tetraethylammonium tetrafluoroborate, melting point:
147-148C, yield: 30%.
Le A 21 974 v -- ,21' --Example 18 ~ Cl E~2 C=HC-H2 COz C 1 C~!l H,C' N CH3 H
In analogy to Example 1, allyl 3~cyano-2,6-di-methyl-4-(2-chlorophenyl)-1,2,3,4-tetrahydropyridine-5-carboxylate was obtained by reduction of allyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-5-carboxylate at a mercury electrode in methanol/tetraethyl-ammonium tetrafluoroborate, melting point: 158-159C, yield: 35X.
Example 19 f~, ~ Cl HIC-C-O~C ~ CN
C~3 11 1 H,C '~N~ C~3 H
In analogy to Example 1, tert.-butyl 3-cyano-2,6-dimethyl-4-~Z-chlorophenyl)-1,2,3,4-tetrahydropyridine-5-carboxylate was obtained by reduction of tert~-butyl 3-cyano-1,4-d;hydro-2,6-dimethyl-4-(2-chlorophenyl)-pyri-dine-5-carboxylate at a mercury cathode in methanol/tetra-ethylammonium tetrafluoroborate, melting point: Z04-205C, yield: 32%.
~ CF, ~,COH2CH2CO2C ~ CN
H,C N CH, In analogy to Example 1, 2-methoxyethyl 3-cyano-Le A 21 974 , ~."
2,6-dimethyl-4-(2-trifluoromethylphenyl)-1,2,3,4-tetra-hydropyridine-5-carboxylate was obtained by reduction of 2-methoxyethyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-(2-tri-fluoromethylphenyl)-pyridine-5-carboxylate at a mercury cathode in a 1:1 mixture of methanol/acetonitrile/tetra-ethylam~on;um tetrafluoroborate, melting po;rt: 182-183C, yield: 54%.
Example 21 Cl H,CO2C~ ~ CN
11 ~
H3C N'-`CH3 H
In analogy to Example 1, benzyl 3-cyano-2,6-di-methyl-~-t2-chlorophenyl)-1,2,3,4-tetrahydropyridine-5-carboxylate was obtained by cathodic reduction of benzyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyri-dine-5-carboxylate at a mercury electrode in methanol/
tetraethylammonium tetrafluoroborate, melting point:
194-196C, yield: 45~.
H 2 CoH2cH 2 C2 C ~ CN
H,C W C~3 .
In analogy to Example 1, 2-benzyloxyethyl 3-cyano-2,6-dimethyl-4-t2-chlorophenyl)-1,2,3,4-tetrahydropyridine-5-carboxylate was obtained by cathodic reduction of 2-benzy-loxyethyl 3-cyano-1,4-dihydro-2,6-dimethyl--4-(2 chloro-phenyl)-pyridine-5-carboxylate at a mercury electrode ;n methanol/acetonitrile/tetrae~hylammonium tetrafluoro-borate, melting point: 88-90C, yield: 25%.
Le A 21 974 -- ~ZS~Z~'70 I ,~. ' , .
Example 23 ~ Cl NC-H2 CH;I CO, C ~X C~J
H,C N CR}
E~
In analogy to Example 1, 2-cyanoethyl 3-cyano-2,6-dimethyl-4-(2-chlorophenyl)-1,203,4-tetrahydropyri-S dine-5-carboxylate was obtained by reduction of 2-cyano-ethyl 3-cyano-1,4-dihydro-2,6-dimethyl-4-(2-chlorophenyl)-pyridine-5-carboxylate at a mercury cathode in methaol/
tetraethylammonium tetrafluoroborate, melt;ng po;nt:
189-191C, y;eld: 25X.
Exa.mp~e 2.4 ~ Cl H3C0 2 C ~ CN
~ I
H,C N CH3 H
In analogy to Example 1, methyl 3-cyano-2,6-di-methyl-4-(2,3-d;chlorophenyl~-1,2,3,4-tetrahydropyr;d;ne-5-carboxylate was obta;ned by reduct;on of methyl 3-cyano~
1,4-d;hydro-2,6-d;methyl-4-(2,3-dichlorophenyl)-pyr;dine-5-carboxylate at a mercury cathode in methanol/tetraethyl-ammon;um tetrafluoroborate, melt;ng point: 238-240C~
y;eld: 45X.
2û
Le A 21 974
Claims (14)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A 1,2,3,4-tetrahydropyridine of the formula in which X represents the nitrile group or the radical -COOR6, R6 being defined below, R1 represents phenyl, naphthyl or pyridyl, the phenyl or naphthyl ring being optionally substituted by 1 or 2 identical or different substituents from the group consisting of phenyl, straight-chain or branched alkyl having 1 to 8 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, alkoxy having 1 to 4 carbon atoms, tri-tetra-and pentamethylene, dioxamethylene, halogen, trifluoromethyl, trifluoromethoxy, difluoromethoxy, tetrafluoroethoxy and cyano, R2 represents a straight-chain, branched or cyclic, saturated or unsaturated hydrocarbon radical having up to 20 carbon atoms, which is optionally interrupted by one oxygen or sulphur atom in the chain and/or which is optionally substituted by halogen, cyano, hydroxyl, .alpha.-,.beta.- or .gamma.-pyridyl, phenyl, phenoxy or phenylthio, it being possible for the phenyl groups to be substituted by halogen, cyano, dialkylamino having 1 to 4 carbon atoms in each alkyl radical, alkoxy having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms, trifluoromethyl or trifluoromethoxy, or by an amino group which in turn is substituted by two identical or different substituents from the group consisting of alkyl having 1 to 4 carbon atoms, phenyl or benzyl, R3 and R5, which are identical or different, each represent hydrogen, a straight-chain or branched alkyl radical having up to 4 carbon atoms, a phenyl radical or a benzyl radical, and R4 represents hydrogen, a straight-chain or branched alkyl radical having up to 4 carbon atoms which is optionally interrupted by an oxygen atom, a phenyl radical or a benzyl radical, R6, when present, is as defined for R2 and maybe the same as, or different from, R2 or a salt thereof with a physiologically tolerated acid.
2. A compound or salt according to claim 1 in which X is -COOR6 and R6 is as defined in claim 1.
3. A compound according to claim 1 or 2 in which R1 represents phenyl optionally substituted by one or two identical or different substituents from the group consisting of fluorine chlorine, cyano, trifluoromethyl, trifluoromethoxy, alkyl having 1 to 4 C atoms, alkoxy having 1 to 2 C atoms, tetramethylene or phenyl, R2 represents a straight chain, branched or cyclic alkyl or alkenyl radical having up to 12 carbon atoms which is optionally interrupted by an oxygen atom in the chain and/or which is optionally substituted by fluorine, chlorine, cyano, hydroxyl, phenyl, phenoxy or an amino group which in turn is substituted by two identical or different substituents from the group con-sisting of alkyl having 1 to 4 C atoms or benzyl, R3 and R5 are identical or different and each represent alkyl having 1 to 2 C atoms, and R4 represents hydrogen, alkyl having 1 -to 4 C atoms or benzyl.
4. A compound according to claim 2, in which R1 denotes phenyl, chlorophenyl, tolyl, trifluoromethylphenyl, methoxyphenyl, cyanophenyl, trifluoromethoxyphenyl, dichlorophenyl or chloro-fluorophenyl, R2 denotes methyl, ethyl, allyl, t-butyl, methoxyethyl, benzyl, benzyloxyethyl or cyanoethyl, R3 and R5 denote methyl, R4 denotes hydrogen and R6 denotes methyl.
5. The compound dimethyl 2,6-dimethyl-4-(2-trifluoromethyl-phenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate or a salt thereof with a physiologically tolerated acid.
6. The compound dimethyl 2,6-dimethyl-4-(2,3-dichlorophenyl)-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate or a salt thereof with a physiologically tolerated acid.
7. The compound dimethyl 2,6-dimethyl-4-phenyl-1,2,3,4-tetrahydropyridine-3,5-dicarboxylate or a salt thereof with a physiologically tolerated acid.
8. A process for preparing a 1,2,3,4-tetrahydropyridine of the general formula (I) as defined in claim 1 or a salt thereof with an appropriate physiologically tolerated acid, which process comprises electrochemically reducing a) a dihydropyridine compound of the formula II
(II) in which R1, R2, R3, R4, R5 and X have the meanings given in claim 1, or b) a pyridine compound of the formula III
(III) in which R1, R2, R3, R5 and X have the meanings given in claim 1, the reduction being effected at a cathode in the presence of an electrolyte and, if required, converting the obtained compound of formula I into a salt with an appropriate physiologically tolerated acid.
(II) in which R1, R2, R3, R4, R5 and X have the meanings given in claim 1, or b) a pyridine compound of the formula III
(III) in which R1, R2, R3, R5 and X have the meanings given in claim 1, the reduction being effected at a cathode in the presence of an electrolyte and, if required, converting the obtained compound of formula I into a salt with an appropriate physiologically tolerated acid.
9. A process according to claim 8, wherein a pool of mercury is used as the cathode and a platinum plate or graphite is used as the anode.
10. A process according to claim 8, wherein a protic solvent is used.
11. A process according to claim 8, wherein reduction is carried out at a temperature of 0-50°C.
12. An antihypertensive composition which comprises an amount of a compound of claim 1 effective in the treatment of hypertension, and a pharmaceutically acceptable carrier.
13. A composition according to claim 12, in the form of a tablet, capsule or pill containing a unit dose.
14. A method of preparing an antihypertensive composition, which method comprises the step of incorporating a compound according to claim 1 as active ingredient in the composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3239273.7 | 1982-10-23 | ||
| DE19823239273 DE3239273A1 (en) | 1982-10-23 | 1982-10-23 | TETRAHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS |
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| CA000439471A Expired CA1252470A (en) | 1982-10-23 | 1983-10-21 | Tetrahydropyridines, process for their preparation and their use in medicaments |
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| US (2) | US4568681A (en) |
| EP (1) | EP0110073B1 (en) |
| JP (1) | JPS5993048A (en) |
| AT (1) | ATE28076T1 (en) |
| CA (1) | CA1252470A (en) |
| DE (2) | DE3239273A1 (en) |
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| DE4342196A1 (en) * | 1993-12-10 | 1995-06-14 | Bayer Ag | New 4-phenyl-substituted 1,4-dihydropyridines |
| DE3414801A1 (en) * | 1984-04-19 | 1985-10-24 | Bayer Ag, 5090 Leverkusen | 4- (NITROPHENYL) TETRAHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS A MEDICINAL PRODUCT |
| US4678796A (en) * | 1984-11-30 | 1987-07-07 | Warner-Lambert Company | 2-alkylidene derivatives of 1,2,3,4-tetrahydropyridine-2,5-pyridine carboxylic acid dialkyl esters useful for treatment of cardiovascular disorders |
| NL8503262A (en) * | 1984-12-10 | 1986-07-01 | Sandoz Ag | 1,4-DIHYDROPYRIDINE DERIVATIVES, PROCESS FOR PREPARING THESE DERIVATIVES AND PHARMACEUTICAL PREPARATIONS CONTAINING THEM. |
| FI862343A (en) | 1985-06-17 | 1986-12-18 | Warner Lambert Co | FRAME FOR THE PREPARATION OF THERAPEUTIC NETWORK 1,4-DIHYDROPYRIDIN INFOERING. |
| US4788203A (en) * | 1985-11-26 | 1988-11-29 | Merck & Co., Inc. | Cyclized N-substituted-tetrahydropyridine compounds, useful in the treatment of cardiovascular disorders |
| US4732898A (en) * | 1986-04-29 | 1988-03-22 | Warner-Lambert Company | 2-(2-aryl-2-oxoalkylidene) analogs of-3,5-pyridinedicarboxylic acid dialkyl esters useful for treatment of cardiovascular disorders |
| DE3700307A1 (en) * | 1987-01-08 | 1988-07-21 | Bayer Ag | TETRAHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN MEDICINAL PRODUCTS |
| US5337085A (en) * | 1992-04-10 | 1994-08-09 | Comsat Corporation | Coding technique for high definition television signals |
| ATE146788T1 (en) * | 1992-10-30 | 1997-01-15 | Bayer Ag | 4-HETEROCYCLOPHENYL SUBSTITUTED DIHYDROPYRIDINES |
| US6001857A (en) * | 1992-10-30 | 1999-12-14 | Bayer Aktiengesellschaft | Heterocyclyl substituted dihydropyridines |
| DE4236707A1 (en) * | 1992-10-30 | 1994-05-05 | Bayer Ag | 4-heterocyclyl substituted dihydropyridines |
| ES2193148T3 (en) | 1993-12-10 | 2003-11-01 | Bayer Ag | 1,4-DIHYDROPIRIDINES REPLACED WITH PHENYLLUS WITH BRAIN ACTIVITY. |
| DE4342193A1 (en) * | 1993-12-10 | 1995-06-14 | Bayer Ag | Aryl substituted alkoxycarbonyl-1,4-dihydropyridine-5-carboxylic acid esters |
| EE03192B1 (en) * | 1993-12-10 | 1999-06-15 | Bayer Aktiengesellschaft | Isopropyl (2-methoxyethyl) -4- (2-chloro-3-cyanophenyl) -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate, its enantiomers and intermediate, methods for their preparation and use |
| CN1261348A (en) | 1997-04-25 | 2000-07-26 | 味之素株式会社 | Dihydropyridine derivatives |
| US5992637A (en) * | 1997-07-14 | 1999-11-30 | Southpac Trust International, Inc. | Packaging material |
| JP2011506440A (en) * | 2007-12-14 | 2011-03-03 | メルク・シャープ・エンド・ドーム・コーポレイション | Mineralocorticoid receptor modulator |
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|---|---|---|---|---|
| DE2658804A1 (en) * | 1976-12-24 | 1978-07-06 | Bayer Ag | Compsn. with circulatory and cardiac activity - contains a 3-cyano-1,2-di:hydro-pyridine deriv. |
| DE3022030A1 (en) * | 1980-06-12 | 1981-12-17 | Bayer Ag, 5090 Leverkusen | 4-THIAZOLE or 4-IMIDAZOLE-SUBSTITUTED, 1,4-DIHYDROPYRIDINE, METHOD FOR THE PRODUCTION THEREOF AND THE MEDICINAL PRODUCTS CONTAINING THEM |
| GR74919B (en) * | 1980-07-16 | 1984-07-12 | Rhone Poulenc Agrochimie |
-
1982
- 1982-10-23 DE DE19823239273 patent/DE3239273A1/en not_active Withdrawn
-
1983
- 1983-10-03 US US06/538,683 patent/US4568681A/en not_active Expired - Fee Related
- 1983-10-12 AT AT83110160T patent/ATE28076T1/en active
- 1983-10-12 EP EP83110160A patent/EP0110073B1/en not_active Expired
- 1983-10-12 DE DE8383110160T patent/DE3372287D1/en not_active Expired
- 1983-10-21 CA CA000439471A patent/CA1252470A/en not_active Expired
- 1983-10-21 ES ES526673A patent/ES526673A0/en active Granted
- 1983-10-22 JP JP58196967A patent/JPS5993048A/en active Pending
-
1984
- 1984-08-24 US US06/644,093 patent/US4559350A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| DE3372287D1 (en) | 1987-08-06 |
| ES8406195A1 (en) | 1984-07-01 |
| DE3239273A1 (en) | 1984-04-26 |
| EP0110073B1 (en) | 1987-07-01 |
| US4559350A (en) | 1985-12-17 |
| ES526673A0 (en) | 1984-07-01 |
| US4568681A (en) | 1986-02-04 |
| EP0110073A1 (en) | 1984-06-13 |
| ATE28076T1 (en) | 1987-07-15 |
| JPS5993048A (en) | 1984-05-29 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |